Infection https://doi.org/10.1007/s15010-020-01521-5 REVIEW Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T‑cell therapy: a position paper Ibai Los‑Arcos1,2 · Gloria Iacoboni3 · Manuela Aguilar‑Guisado5 · Laia Alsina‑Manrique6 · Cristina Díaz de Heredia7 · Claudia Fortuny‑Guasch8 · Irene García‑Cadenas9 · Carolina García‑Vidal10 · Marta González‑Vicent11 · Rafael Hernani12 · Mi Kwon13 · Marina Machado14 · Xavier Martínez‑Gómez15 · Valentín Ortiz Maldonado16,17 · Carolina Pinto Pla18 · José Luis Piñana19 · Virginia Pomar20 · Juan Luis Reguera‑Ortega21 · Miguel Salavert22 · Pere Soler‑Palacín23 · Lourdes Vázquez‑López24 · Pere Barba3,4 · Isabel Ruiz‑Camps1,2 Received: 18 June 2020 / Accepted: 29 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignan- cies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy. Keywords Chimeric antigen receptor · Diffuse large B-cell lymphoma · B-cell acute lymphoblastic leukemia · Bacterial infections · Viral infections · Fungal infections Introduction of lymphoid malignancies, axicabtagene ciloleucel (axi-cel) or ­Yescarta® (Gilead Inc., USA) for the treatment of diffuse Chimeric antigen receptor (CAR) T-cell therapy is one of large B-cell lymphoma (DLBCL) and primary mediastinal the most promising emerging treatments for hematologic B-cell lymphoma (PMBCL), and tisagenlecleucel (tisa-cel) malignancies [1, 2]. Although there are several therapeutic or ­Kymriah® (Novartis Inc., Basel, Switzerland) for the targets under development, CD19 is the most widely used treatment of DLBCL and B-cell acute lymphoblastic leu- antigen for the treatment of B-cell malignancies. Recently, kemia (B-ALL). two CAR T products have been approved for the treatment Most of the patients receiving CAR T therapy will develop fever after infusion [3], mainly due to cytokine release syndrome (CRS), a systemic inflammatory condition Members of the Infection Prevention in CAR T-cells Study Group mediated by CAR T-cells. This syndrome is often indistin- are listed in acknowledgements. guishable from an infection as it usually includes tachycar- * Pere Barba dia, tachypnea and hypotension [4]. CRS is produced by pbarba@vhio.net endothelial activation and overproduction of inflammatory Extended author information available on the last page of the article cytokines such as interferon γ (IFN-γ), interleukin 6 (IL-6) 13 Vol.:(0123456789) I. Los‑Arcos et al. and tumor necrosis alpha (TNF-α) [5]. Increased plasma Most patients had an infection without microbiological levels of these cytokines have also been observed in sepsis isolation, followed by bacterial and viral infections, mostly [6]. Some studies have looked into the cytokine results in with respiratory tract involvement. Logue et al. described both CRS and infection trying to find a different biomarker a similar incidence of infections, 37% in the first 30 days, profile. One of these studies did not find any differences in being Clostridioides difficile colitis the most frequent (14% the cytokine profile of these two groups of patients [7]. How- of all patients) [11]. Recently, Wudhikarn et al. reported ever, another study was able to develop a prediction model in patients with DLBCL a cumulative incidence of 63% of including three cytokines (IL-8, IL-1β and IFN-γ) to detect infections at 1 year [12]. life-threatening infections [8]. In any case, more research Finally, Cordeiro et al. [13] reported an infection density is needed to identify specific biomarkers differentiating the of 0.55 infections/100 days at risk (2.08/patient year) within two clinical settings. the first 90 days after CAR T-cell infusion in adult patients. Since only a limited number of patients have been treated Eighty percent of them were treated in the outpatient set- with CAR T-cell therapies, there are scarce data on inci- ting. Twenty-four percent of these events had a microbio- dence, risk factors and preventive strategies [8, 9] in these logical etiology, mainly bacterial (60%), viral (31%) (mostly patients. We present herein recommendations on the man- respiratory viruses) and fungal (9%) infections. Moreover, agement of infections for patients receiving CAR T cells. infection was the main cause of non-relapse mortality (8/12 cases, 66.7%) in DLBCL patients treated with axi-cel in the Methodology standard-of-care setting [14]. A multidisciplinary team from the hospitals designated by the Spanish Ministry of Health to deliver CAR T-cell ther- Risk factors apy contributed to this set of recommendations for preven- tion and management of infections. To implement clinical Patient-, disease- and construct-related factors as well as decisions, these recommendations should always be con- treatment-related variables can increase the risk of infec- sidered together with the underlying disease, previous treat- tion [7, 12, 15]. Age has been identified as a risk factor for ments and local epidemiology. developing CRS and neurological events after CAR T-cell The preparation and writing of this manuscript involved therapy [16], but it has not been clearly associated with an hematologists, infectious diseases specialists and pedia- increased risk of infection. Baseline disease (being higher tricians. We performed a systematic literature search in in ALL than in DLBCL), type and number of previous anti- PubMed, using the search filters “CAR T AND infection”, tumor regimens have also been identified as potential risk “CAR T AND follow-up”, “CAR T AND prophylaxis”, factors for the development of infections. The dose of CAR “CAR T AND hypogammaglobulinemia” and “CAR T AND T-lymphocytes [15], as well as type and intensity of lym- vaccines”. The final document was reviewed and approved phodepleting chemotherapy can also contribute to the devel- by all authors. Table 1 is a summary of the most important opment of infections after therapy [15]. Neutropenia, which recommendations of this document. has been described in up to 80% of the patients within the first month after infusion [17] can also increase the risk of infection in these patients, especially in those with long-term Incidence and risk factors persisting cytopenias [13, 17, 18]. CRS itself through endothelial damage and its treatment Incidence with tocilizumab and/or corticosteroids can favor and/or complicate some infections [7, 15]. Tocilizumab has been Data regarding the incidence of infections in these patients associated with increased risk of infection in patients with are scarce, and this may vary depending on the underlying rheumatoid arthritis [19]. In patients receiving CAR T cells, disease and the CAR T construct. The reported incidence its use has also been associated with a higher risk of infec- of any infection in patients treated with tisa-cel for B-cell tion. Since tocilizumab is used in most cases of severe CRS precursor ALL [9] and DLBCL is 65% and 54%, respec- it is difficult to differentiate between CRS itself and its treat- tively. Serious infections (grade 3 or higher) occurred in ment as the direct cause of infections. In patients with mild 44% and 32% of ALL and DLBCL patients, respectively, CRS (grade 1) the use of tocilizumab was not associated most of them occurring within the first 8 weeks after CAR with increased risk of infection in a recent study [20]. In T-cell infusion. Regarding axi-cel, 35% and 38% of patients some cases, anakinra (IL-1R inhibitor) has been used for with relapsed/refractory DLBCL included in the ZUMA-1 the treatment of CRS and neurotoxicity [21]; this drug could trial developed febrile neutropenia and infections, respec- also potentially increase the risk of infection [22, 23], but tively [10]; 25% of these infections were grade 3 or higher. clinical experience in these patients is scarce. 13 Table 1  Prophylaxis recommendations in CAR T-cell recipients Type of infection Indication Drugs and dosages (adults) Drugs and dosages (children) Duration Bacterial infections Routine prophylaxis not recommended Viral infections HSV seropositive patients Acyclovir 400-800 mg every 12 h po Acyclovir At least 60–100 days after CAR T-cell (or 5 mg/kg every 12 h iv) OR: 20 mg/kg every 8 h (MD 800 mg infusion and even longer in high-risk every 12 h) patients (recent allogenic HSCT, ster- IV: 250 mg/m2 every 8 h; oid/tocilizumab therapy…) Invasive fungal infections Fluconazole in all cases and prophy- Fluconazole 400 mg every 24 h Fluconazole: 3–6 mg/kg (single daily Until neutrophil recovery laxis of filamentous fungi if two or For filamentous fungi: dose) orally/iv (MD 400 mg) more risk factors are present: Posaconazole (tablets) 300 mg every For filamentous fungi: 1. ≥ 4 prior treatment lines 12 h on first day and then 300 mg Posaconazole oral solution: 2. Neutropenia (< 500mm3) prior to the once daily po < 34 kg: 4 mg/kg every 6 h (first day) infusion Nebulized liposomal amphotericin B and 4 mg/kg every 8 h thereafter 3. CAR-T doses > 2 × 107/kg 24 mg once a week ≥ 34 kg: 200 mg every 6 h (first day) 4. Previous IFI Micafungin 100 mg once daily and 200 mg every 8 h thereafter 5. Tocilizumab and/or steroids ≥ 13 years (tablets) 300 mg every 12 h (first day) and 300 mg once daily thereafter Nebulized liposomal amphotericin B Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… 24 mg once a week Micafungin—3–4 mg/kg 2 days a week (MD: 300 mg) Pneumocystis jirovecii All cases Trimethoprim sulfamethoxazole Cotrimoxazole 5 mg TMP/kg/day 1 week before the infusion and until 800/160 mg three times pw or aero- every 12–24 h 3 days a week orally CD4 count > than 200 cells/μL solized pentamidine (300 mg) every (MD:160/800 mg) 3–4 weeks Pentamidine IV:4 mg/kg every 28 days (MD:300 mg) h hours, HSV herpes simplex virus, IFI invasive fungal infection, iv intravenous, MD maximum dose, po oral dosing, pw per week, TMP trimethoprim, μL microliter 13 I. Los‑Arcos et al. Finally, CAR T therapy causes a variable-length B-cell Ig, including 17 (44%) of the 39 patients with longer lasting aplasia (while circulating CAR T persists, which varies responses [10, 29]. from a few days to several years) [24, 25] and a progressive In conclusion, the incidence and severity of hypogamma- secondary hypogammaglobulinemia, exposing them to life- globulinemia varies across studies, being higher in patients threatening infections, especially in pediatric patients with with ALL. Furthermore, a recent study confirmed the per- ALL [26]. sistence of circulating CD19 negative plasma cells in a small In summary, risk factors for bacterial, fungal, and viral series of patients with ALL and chronic lymphocytic leu- infections are neutropenia, B-cell aplasia/hypogammaglobu- kemia (CLL); the humoral response in this case could be linemia and impaired cellular immunity, along with the use long-lasting despite treatment with CAR T [30]. of tocilizumab and/or corticosteroids for the treatment of CRS and/or neurotoxicity (Fig. 1) [7, 15, 26]. Management of hypogammaglobulinemia Although there are some published recommendations [25, Hypogammaglobulinemia 31], there is no clear consensus on immunoglobulin replace- ment therapy in patients who have received CAR T-cell In the B-cell ALL setting, a study with 43 pediatric patients therapy. The subset of patients, timepoints and schedule are and young adults showed a 90% prolonged B-cell aplasia the most frequently unresolved questions. Therefore, our rec- after therapy [27]. ommendations are based on clinical experience from other In the ELIANA trial, all the patients who responded neoplastic diseases (such as CLL or multiple myeloma) and developed B-cell aplasia and most of them received replace- hematopoietic stem cell transplantation (HSCT). In children, ment therapy with immunoglobulins according to the local especially when they are under 10 years of age, the protocols policy. The median recovery time had not yet been reached, of agammaglobulinemia are recommended [32]. with a probability of 83% of maintaining B-cell aplasia at 6 months after infusion [18]. A single-center study, con- Recommendations in the adult population ducted at the University of Pennsylvania including 28 patients, monitored the levels of immunoglobulins after CAR 1. Monitoring T-cell therapy in 12 ALL patients. Two of these patients   All patients should have a baseline assessment of received replacement treatment from 12 to 22 months after lymphocyte subsets and immunoglobulin levels prior the infusion due to recurrent sinopulmonary infections. The to lymphodepleting chemotherapy. After the infusion, remaining ten patients did not receive substitute treatment, the time points for assessment of lymphocyte subsets and recovered IgG count at a median of 18 months after the (CD4+) and immunoglobulins should be monitored: infusion [28]. Seventy-five percent of the patients diagnosed • Monthly until the 6th month after infusion. with non-Hodgkin lymphoma included in the ZUMA-1 [10] • After the first 6 months, it will be done according to trial achieving disease response after axi-cel showed restored clinical criteria. In general, among those patients with- B-lymphocyte count 24 months after the infusion, and recov- out hypogammaglobulinemia, immunoglobulin levels ery began in some cases at 9 months. Thirty-three (31%) of should be assessed at least twice a year (and immuno- the 108 infused patients received replacement therapy with globulin subclasses monitored annually). Fig. 1  Risk factors for infection in patients receiving CAR T cells 13 Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… 2. Replacement therapy Bacterial infections The incidence of bacterial infection described in patients • An individual IgG level has been proposed, which receiving CAR T therapy ranges from 10 to 43% [7, 15, 18, should be adapted to each patient over time, being the 39]. This incidence is possibly higher taking into account one that improves their clinical status and reduces the that some bacterial infections could be underdiagnosed in percentage of infections [33]. the context of CRS. Incidence of grade 4 and 5 bacterial • Substitution therapy should be considered in two other infections < 6% [7, 18, 40]. situations: o Deficit of some immunoglobulin subclass. Prevention/prophylaxis and management o Absence of seroconversion after vaccination of teta- of bacterial infection nus, diphtheria or pneumococcus. Our general recommendations for the prevention of bacte- • In overweight patients (BMI ≥ 30 kg/m 2 or if real rial infection in these patients are: weight > 20% of the ideal weight), the dose should be adjusted to the ideal adjusted weight according to • Patients with an active, uncontrolled infection should the following formula: ideal adjusted weight = ideal not start treatment with CAR T therapy until the infec- weight + 0.4 [real weight (kg) − ideal weight]. tion has resolved. This includes both the lymphodeplet- • If the patient has a selective IgA deficit, even though ing chemotherapy and the CAR T-cell infusion. adverse events due to specific anti-IgA are less frequent • Antibacterial prophylaxis is not recommended. than previously thought [34], priority should be given • If the patient develops fever or infectious symptoms, to products with the lowest possible amount of IgA or even if CRS is suspected, microbiological samples to subcutaneous administration [35]. should be collected and empiric antibiotic treatment • If substitution is necessary, 400–600 mg/kg every initiated according to the local protocol. The empiric 3–4 weeks [36] is accepted as the starting dose, aim- antibiotic therapy should take into account the individ- ing to reach an IgG trough above 400 mg/dL in adults. ual risk of the patient and the local antibiotic resistance • If a patient develops frequent respiratory infections, profile, always including Pseudomonas aeruginosa. despite monthly replacements, the physician should • The clinical situation should be reassessed 48 h after consider raising the dose, reducing the administration the onset of fever. If there is no sign of active infec- interval or switching to subcutaneous formulations. tion, the cultures are negative, the diagnosis of CRS is highly probable and the patient is afebrile or stable, the withdrawal of the antibiotic should be considered. Recommendations in pediatric population • There are no differences regarding prophylaxis and treatment in the pediatric population. • Replacement therapy should start ~ 1 month after CAR T infusion in all patients [24, 25]. • The recommended replacement dose is 0.5 g/kg/ monthly [25, 37, 38], aiming to reach the normal range Viral infections for the child’s age. • In children, it may be advisable to achieve higher Herpesviridae IgG trough values (800 mg/dL) [38], especially under 10 years of age and when there are associated risk fac- Incidence and available evidence tors such as baseline pulmonary pathology, history of total body irradiation or added immunosuppression by Herpes simplex virus (HSV) and VZV In European countries, chronic graft versus host disease. the seroprevalence of HSV type 1 is around 80% in adults • Replacement therapy should last as long as B-cell [41]. Hence, reactivation after immunosuppressive therapy aplasia. If there is a persistent low IgA or IgM value in hematological patients is very frequent in the absence of replacement therapy should be maintained. prophylaxis. • Once there is B-cell recovery, the decision to stop There are no specific data on the incidence of compli- immunoglobulin replacement should be evaluated on cations associated with HSV after treatment with CAR T. a case-by-case basis. 13 I. Los‑Arcos et al. It should be noted, however, that most patients received • Neither directed prophylaxis nor routine monitoring of prophylaxis with acyclovir or valacyclovir [7]. HHV-6 PCR seems to have any role in these patients. Regarding varicella zoster virus (VZV) infection, its • In the pediatric population who has previously undergone incidence in CAR T recipients is also unknown. Patients an HSCT, the recommendation is to monitor CMV, ade- receiving other immunosuppressive therapies, such as allo- novirus, EBV and HHV-6 once or twice a week. If there geneic HSCT, carry a high risk of developing this infection is a positive CMV PCR result, treatment with ganciclovir (15–50% after 5 years of treatment/transplantation). Note- or foscarnet should be initiated. worthy, a case of early reactivation has been described in a patient who did not receive acyclovir prophylaxis [15]. Hepatotropic viruses Cytomegalovirus (CMV) In western European countries the Patients receiving B-cell-targeted therapy like rituximab CMV-positive adult population is around 70%. Two stud- are at a higher risk for hepatotropic viral reactivation [42]. ies [7, 15] have reported the incidence of CMV infection/ Safety of CAR T-cell therapy in patients with chronic hepa- disease in patients treated with CAR T. Among the 186 titis B virus (HBV) or hepatitis C virus (HCV) infection is patients included in both studies, two presented a reactiva- scarce, since most of the trials excluded patients with active, tion of the virus detected by plasma PCR and one patient latent or past infections. A few cases of patients with very had a CMV pneumonia, diagnosed between days 29 and 90 low or undetectable HBV and HCV viral load were suc- post-infusion. cessfully treated with CAR T cells [43]. However, a fatal There are no published data on the monitoring of viremia case of VHB reactivation was described in a patient carrying or the use of prophylaxis in this context. HBsAg who discontinued antiviral prophylaxis [44]. Screening for HBV, including HBV surface antigen Epstein–Barr virus (EBV) Only one study [15] including (HBsAg), core antibody (anti-HBc) and surface antigen 133 adult patients receiving CAR T-cell therapy for differ- antibody (anti-HBs), together with HCV and HIV is man- ent refractory or relapsed B-cell malignancies described the datory. If a patient is HBsAg positive or HBsAg negative but incidence of EBV infection in this context. A single patient, anti-HBc positive, an HBV DNA study should be performed, who developed CRS grade 4, presented a positive PCR in irrespective of anti-HBs [45–48]. Antiviral treatment with both plasma and cerebrospinal fluid. entecavir is recommended in HBsAg-positive patients or patients with detectable HBV DNA before starting CAR T Human herpesvirus 6 (HHV‑6) Its seroprevalence is very cells and during at least 6–12 months after infusion [49–51]. high in the general population (> 95%). At present, no study The duration should be decided on a case-by-case basis. In has provided data on the incidence of complications related anti-HBc positive patients, with negative HBsAg and HBV to HHV-6 in this context. DNA, antiviral treatment or monitoring of HBV DNA every 1–3 months can be performed [50]. Patients with hepatitis C infection should be considered for antiviral treatment taking Prevention/prophylaxis and management into account the patient’s liver function and clinical situa- tion [52]. • Acyclovir prophylaxis should be administered in patients It is also advisable to perform a hepatitis A screen- with a positive baseline serology, from the start of lym- ing, even though there are no specific data in this context. phodepleting chemotherapy until a minimum of 60 to Regarding HDV, patients with anti-HBc antibodies should 100 days after infusion (Table 1). Our recommendation be screened with anti-HDV serology, and HDV RNA should is to maintain the prophylaxis up to + 100 days after infu- be performed if antibodies are positive [49]. HEV virus is sion, and even longer in subgroups of patients considered an enteric transmitted infection usually subclinical and at high risk (history of recent allogeneic transplantation, self-limited. However, chronic disease has been reported in adverse events related to CAR T cells that required ster- immunocompromised patients and treatment with ribavirin oid/tocilizumab treatment…). In seronegative patients has been suggested in this setting [49]. If a patient experi- for HSV and VZV, prophylaxis is not necessary. When ences acute liver test abnormalities during CAR T therapy, the serological status is unknown, prophylaxis should be hepatotropic virus should be analyzed. used routinely. • The monitoring of CMV and EBV DNAemia should only Human immunodeficiency virus (HIV) be carried out for academic purposes, the results should not determine the start of preemptive treatment. Simi- Patients diagnosed with HIV infection were excluded from larly, prevention strategies, such as letermovir or rituxi- clinical trials [53], so data in this setting is scarce. The mab, do not seem justifiable at the present time. European Society for Blood and Marrow Transplantation 13 Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… (EBMT) and the Joint Accreditation Committee of ISCT The European Conference on Infections in Leukemia and EBMT (JACIE) practice recommendations have sug- (ECIL) proposed some definitions based on the symptoms gested that pharmaceutical companies could manufacture and PCR results to improve management strategies [66]. CAR T cells for HIV-positive patients if the viral load was undetectable after anti-retroviral treatment [54]. The pub- General prevention/prophylaxis and management lished clinical experience is limited to three patients with of respiratory virus infection HIV successfully treated with CAR T cells without addi- tional toxicity [55, 56]. • We recommend testing only patients with symptoms More data are needed to make specific recommendations of URTI/LRTI, especially looking for the ones which in this setting. Currently, the decision to treat HIV patients have an antiviral treatment (influenza, RSV, ± PIV and should be assessed on a case-by-case basis taking into hMPV). To avoid a delay in diagnosis and treatment, account the viral load and risk of opportunistic infections. rapid detection techniques for influenza and RSV anti- gens are a choice during the period of circulation of these Community‑acquired respiratory viruses (CRV) viruses. However, given their lower sensitivity and speci- ficity, multiplex PCR techniques in the same sample are Infections of the upper and/or lower respiratory tract (URTI/ advisable if rapid detection is negative. LRTI) by community respiratory viruses are one of the • General precautions for preventing the transmission leading causes of morbidity and mortality worldwide with of CRV, including hand washing, personal protective multiple direct and indirect deleterious effects, representing equipment (gloves, gown and mask), and education to a huge economic burden for the health system [57]. Most caregivers and patients should also be implemented in viruses, including influenza, parainfluenza (PIV) and metap- the CAR T setting. Health-care personnel and caregiv- neumovirus (hMPV) have a seasonal predominance, from ers with symptoms of respiratory infection should avoid late autumn to mid spring. The PIV peaks in autumn and close contact with CAR T recipients. spring but is also frequent throughout the year. The severity depends on the type of virus, the age of the patient, the previous immunosuppression and whether it is Recommendations for influenza virus a primary infection or reinfection. The infections produced by these viruses are clinically indistinguishable from each • Influenza vaccination of CAR T recipients and close fam- other. Often, those produced by hMPV are presented in the ily is recommended. form of co-infection with bacteria, fungi, and other CRVs, • Patients with confirmed influenza before the start of CAR as well as CMV. These co-infections have a high mortality T therapy should receive antiviral treatment and delay rate [58, 59]. start of lymphodepleting chemotherapy at least 2 weeks A recently published risk scale developed in the setting or until resolution of symptoms. of allo-HSCT recipients identified three separate risk groups • All patients with confirmed or probable influenza after (low, intermediate and high) with an increasing risk of pro- CAR T infusion should receive treatment, regardless of gression to lower respiratory tract and mortality [60] Even the time elapsed since the infusion. though this risk scale, known as the “immunodeficiency • The first-line treatment for influenza is oseltamivir. In score index” (ISI), was designed to predict these compli- severe cases of influenza, when the intestinal absorption cations in patients with respiratory syncytial virus (RSV) of the drug is decreased (mucositis and/or diarrhea) and infection, it has proven useful in other types such as influ- inhalation of zanamivir is not possible, intravenous per- enza, coronavirus and adenovirus [61–63]. The variables amivir or zanamivir could be alternatives. included in ISI are neutropenia (< 500/mm3), lymphopenia • In patients with persistent symptoms, after ruling out (< 200/mm3), age > 40 years, graft versus host disease, ster- oseltamivir resistance, treatment and isolation should be oid use, myeloablative chemotherapy, and allo-HSCT. How- maintained until symptoms are resolved and/or PCR is ever, this scale has not been validated in patients receiving negative. CAR T-cells. The incidence of CRV infections after anti-CD19 CAR Recommendations for respiratory syncytial virus (RSV) T therapy in two studies [7, 15] was around 6% within the first 30 days, and rose to 28% within the first 6 months after • In patients with respiratory symptoms and a proven RSV infusion [7]. Several studies, carried out in other high-risk infection before the start of CAR T therapy, it is advis- populations with increased risk, showed that the presence of able to start antiviral treatment and delay the start of hypogammaglobulinemia was associated with an increased lymphodepleting chemotherapy at least 2 weeks or until risk of mortality due to CRV [64, 65]. symptoms resolve. 13 I. Los‑Arcos et al. • In patients with LRTI who have received CAR T therapy lack of data in patients receiving CAR-T cells, it seems within the previous 90 day and who present lymphope- reasonable to take a similar approach in patients develop- nia, neutropenia or hypogammaglobulinemia, ribavirin ing severe SARS-CoV-2. is recommended, orally or intravenously, in increasing During the SARS-CoV-2 pandemic, health-care systems doses up to a maximum of 30 mg/kg/day divided in three suffered a high incidence of admissions due to this disease doses ± IVIG. with overuse of intensive care units (ICU) in some cases. • Children under 2 years of age, especially those with a In this context, patient selection should be conducted care- history of respiratory pathology, prophylaxis with mono- fully, while still allowing patients with good performance clonal antibodies against RSV could be considered. status and limited comorbidities to be considered for CAR T-cell therapy [79]. CAR T-cell treatment candidates should follow pre- Recommendations for other CRV ventive measures such as strict hygiene procedures and social distancing [77, 79]. Moreover, symptoms of SARS- • In the absence of effective agents against VPI [67–69] CoV-2 infection should be assessed and screening of this and hMPV [58, 59] treatment with ribavirin ± IVIG is infection with PCR should be made at relevant time points advised in patients with one or more risk factors for pro- regardless of symptoms, including before apheresis, lym- gression to LTRI and in patients with UTRI. The possible phodepleting chemotherapy and CAR T-cell infusion in all toxicities of ribavirin, especially myelotoxicity, should be CAR-T cell candidates [79]. taken into account. • There are currently no effective antiviral drugs available for enterovirus, rhinovirus, coronavirus and bocavirus. Other viruses Therefore, recommendations in this setting are limited. Early identification and supportive treatment are impor- Adenovirus (HAdV) tant, together with treatment of associated bacterial and/ or fungal infections. There are no studies on the incidence of HAdV in patients treated with chemo-immunotherapy; however, it can cause serious problems in this population. It usually affects chil- Severe acute respiratory syndrome coronavirus 2 dren or young adults. In vivo or ex vivo T-cell depletion (SARS‑CoV‑2) is the main risk factor for infection in this population [80, 81] and severe lymphopenia (< 200/mm3) is the main risk In December 2019, a new virus named SARS-CoV-2 was factor for mortality [66]. identified in Wuhan, China [70]. The World Health Organi- zation declared the SARS-CoV-2 outbreak a pandemic and Recommendations for HAdV reported on June 1, 2020 more than six million cases with 371,166 deaths [71]. Three stages of the disease have been • PCR monitoring is not routinely recommended in described: an early mild infection, followed by pulmonary adults. In the pediatric population, it should be carried damage and finally a systemic hyperinflammation [72]. High out one to two times per week. Early antiviral therapy levels of pro-inflammatory cytokines and biomarkers includ- with ribavirin is not recommended. Consider treatment ing IL-2, IL-6, IL-7, tumor necrosis-α or d-dimer have been with cidofovir in children, to avoid systemic disease identified in patients with more severe disease. For this rea- [82, 83]. Brincidofovir is an alternative, but currently son, some immunomodulatory agents including tocilizumab as a compassionate use and with possible adverse have been investigated as possible treatment for this disease events such as gastrointestinal toxicity [84]. [72]. • In patients with URTI due to hAdV, measures such Hematological patients with SARS-CoV-2 seem to harbor as isolation, close monitoring, and assessment of risk a dismal outcome [73–75]. Data about SARS-CoV-2 infec- factors for progression to LTRI are recommended. In tion in patients receiving CAR T cells are very limited [73] patients with severe LTRI and at least one risk factor, and do not allow drawing definitive conclusions. antiviral treatment with cidofovir for 2–3 weeks should Several antiviral and immunomodulatory agents are be considered; thereafter, every 2 weeks until complete currently under evaluation for the treatment of this infec- resolution. On the day of administration of cidofovir, tion [76, 77]. In patients with oxygen saturation lower than remember to add hydration and oral probenecid. The 95%, dexamethasone for 10 days as well as remdesivir use of brincidofovir is restricted to intolerance/toxicity for 5 days is recommended in the last Infectious Disease to cidofovir [83]. Society of America (IDSA) guidelines [78]. Despite the 13 Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… Polyomavirus (Polyomavirus hominis 1 and 2) false positive results due to other treatments is high (intra- venous antibiotic treatment, platelet transfusion, nutritional About 80% of the adult population is seropositive against the supplements). The low rate of positive test prediction in this Polyomaviridae virus, including both pathogenic species: context limits its clinical utility and may involve unnecessary Polyomavirus BK (hemorrhagic cystitis) and Polyomavirus diagnostic and therapeutic efforts [89, 90]. It is important to JC (progressive multifocal leukoencephalopathy). Anecdotal analyze each case individually to establish the risk of IFI and cases of BK infections and hemorrhagic cystitis have been implement early diagnostic measures. described after CAR T-cell therapy [7, 15]. In a survey of 52 pediatric and adult centers in the USA, Taking into account the lack of conclusive data on the 87% administered antifungal prophylaxis to patients under- impact of reactivation, this possibility should always be going treatment with CAR T, the vast majority of them only suspected in case of the appearance of hemorrhagic cystitis against yeasts (92% with fluconazole). The duration of this (BK) or atypical neurological symptoms with a multifocal prophylaxis was variable, but in most cases it was stopped demyelination, especially when its presentation is late (JC). at the time of neutrophil recovery [91]. Regarding Pneumo- Routine PCR monitoring in blood and/or urine for BK cystis jirovecii, all centers confirmed the use of prophylaxis, virus does not seem necessary in these patients. mostly with cotrimoxazole. Fungal infections Prevention/prophylaxis and management of IFIs The incidence of invasive fungal infections (IFI) in adult • Routine serum GM monitoring is not recommended. patients with B-cell ALL, non-Hodgkin B-cell lymphoma • Fluconazole 400 mg/24 h is advisable in the neutropenic or CLL treated with CAR T is globally between 5 and phase after lymphodepleting chemotherapy. 10% [7, 85]. In a study including 133 patients with several • If the patient presents at least two of the following high hematological malignancies receiving CAR T-cells, six of risk factors, it is recommended to perform prophylaxis of them (4.5%) developed eight episodes of IFI (5 for non- filamentous fungi until neutrophil recovery (> 500/mm3): filamentous fungi and 3 for filamentous) mostly within the first 28 days after infusion [15]. In this study, the prophylaxis o Four or more prior treatment lines [15]. consisted of fluconazole 400 mg/day when neutrophil count o Neutropenia below 500/mm3 prior to infusion of was below 500/mm3. There were no deaths associated with CAR T. IFI. o Dose of CAR T lymphocytes greater than 2 × 107/kg Four of the 53 adult patients (7.5%) with B-cell ALL [7, 15]. treated at MSKCC developed an IFI in the first 30 days o Previous IFI. after CAR T-cell infusion (1 yeast and 3 filamentous fungi o Administration of tocilizumab and/or steroids. lung infections [2 probable aspergillosis and 1 confirmed   Prophylaxis can be carried out with posacona- mucormycosis]). Of note, 79% of these patients received zole (tablets), nebulized liposomal amphotericin B prophylaxis with micafungin at a dose of 100 mg/day [7]. or micafungin (Table 1). The duration of prophy- The median number of days until IFI was 23. After day 30, laxis after neutrophil recovery should be decided 1 IFI per filamentous fungus was documented. There were on a case-by-case basis, taking into account the no deaths associated with IFI in this study. additional risk factors. Generally, we recommend 1 Recently, the University of Pittsburg documented an inci- month of antifungal prophylaxis after tocilizumab dence of 3% (2/59) of IFI in their CAR T-cell recipients [86]. and/or steroids. In the study of late complications by Cordeiro et al., [13], four fungal infections were recorded (2 Aspergillus spp., 1 • There are no specific data in the pediatric population, but Candida spp. and 1 coccidioidomycosis). antifungal prophylaxis is widely recommended [3] in this Pre-test infection prevalence is a key factor when per- setting with the appropriate dose adjustments (Table 1). forming diagnostic tests, including the determination of • Prophylaxis against Pneumocystis jirovecii is mandatory serum galactomannan (GM) and bronchoalveolar lavage and includes trimethoprim sulfamethoxazole or inhaled (BAL) for detection of invasive aspergillosis (IA) [87]. The pentamidine every 3–4 weeks. Trimethoprim sulfameth- use of effective antifungal prophylaxis in high-risk hemato- oxazole should be started 1 week before the cell infusion logic patients has shown to successfully reduce the incidence and maintained until the CD4+ count is greater than 200 of IA [88]. Asymptomatic monitoring twice a week based on cel/mcL (stop during admission and restart once the cyto- the determination of serum GM is unreliable, since the pre- penias have recovered). Consider pentamidine in cases at test probability of infection is very low and the possibility of risk of increasing the period of neutropenia (Table 1). 13 I. Los‑Arcos et al. Latent infections Vaccination prior to CAR T therapy Patients receiving immunosuppressive therapy should be Inactivated vaccines, due to the potential poor response, will screened for latent infections; with CAR T-cell therapy we be postponed to the post-CAR T stage, with the exception of: take a similar approach. Patients coming from or often trave- ling to endemic countries should be screened accordingly • Influenza in epidemic season. [92]. Specific recommendations are summarized in Table 2. • Anti-pneumococcal conjugate, as patients with B-cell ALL have a high risk of invasive pneumococcal infec- tion. Vaccination of patients receiving CAR T • HBV, especially in susceptible patients with high risk of infection or reactivation, and in areas of high prevalence At present, there are no recommendations regarding the vac- of this infection. cine requirements of adult and pediatric patients treated with • All house contacts of patients should be immunized CAR T [93] therapy. There are no data on immunogenicity, against influenza. Also those susceptible to varicella efficacy, or safety of vaccine administration in this setting. or measles should be vaccinated. In case of vaccination The clinical and immunological status of these patients pre- against rotavirus (only in those younger than 7 months), cludes the use of live and attenuated vaccines [94, 95]. they cannot be in contact with the patient for the follow- As some patients treated with CAR T may have under- ing 4 weeks. gone HSCT (particularly patients with ALL) and may have not been vaccinated after this procedure, the model of vac- Vaccination after CAR T therapy cination after CAR T generally follows allo-HSCT vaccina- tion schedules: the administration of vaccines is not recom- • After CAR T therapy and during the B-cell depletion mended until 3 months (in the case of inactivated vaccines) phase, live or attenuated vaccines should not be admin- or 24 months (in the case of attenuated vaccines, only if istered due to the risk of reactivation of the vaccine no immunosuppression is active) after cell infusion [95]. It strain [97]. Postpone revaccination until the patients have should be noted that during B-cell aplasia and administration recovered from B-cell aplasia. of polyvalent immunoglobulin replacement therapy primary • Regarding inactivated vaccines, and assessing the pos- responses to vaccines may be very limited. Some memory is sible risk–benefit ratio [98], the influenza vaccine is rec- preserved for vaccines received pre-treatment, at the expense ommended annually [93, 94], starting 30 days after CAR of long-lived plasma [30, 96]. T infusion. There are no data confirming that two doses Finally, it is recommended to enhance the immunization produce more immunogenicity than one. of immediate family members and health-care profession- • Specially important during B-cell aplasia, even though als [94]. the effectiveness may be lower, are the pneumococcal conjugate vaccine (some patients have functional asple- nia due to the previous treatments) and influenza (includ- ing family members and cohabitants) [97]. Those vac- cines should be repeated once when the B-cell aplasia is recovered. Table 2  Screening of infectious diseases according to the geographical area: Central and South America Caribbean North Africa and Sub-Saharan Asia Islands Middle-East Africa HIV, HBV, HCV, HSV, CMV, VZV, TG Yes Yes Yes Yes Yes and TP serologies IGRA​ Yes Yes Yes Yes Yes Parasites in feces Yes Yes Yes Yes Yes Strongyloides stercolaris serology Yes Yes Yes Yes Yes Plasmodium spp. PCR Amazonian region Yes No Yes Yes Trypanosoma cruzi serology Yes No No No No Schistosoma mansoni serology Brasil and Venezuela Yes No Yes No CMV cytomegalovirus, HBV hepatitis B virus, HCV hepatitis C virus, HIV human immunodeficiency virus, HSV herpes simplex virus, IGRA​ interferon-gamma release assays, VZV varicella zoster virus, TG Toxoplasma gondii, TP Treponema pallidum 13 Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… Table 3  Vaccine program after CAR T-cell therapy in pediatric or adult patients with a previous HSCT Antigens (vaccines) Time after HSCT Recommended interval between Number of doses doses Diphteria, tetanus and pertussis 6 months (dose 1) 1–2 months 4 (DTPa-dTpa/tD) 7 months (dose 2) 8 months (dose 3) 18 months (dose 4) Poliomielitis (PI) 6 months (dose 1) 1 month 4 7 months (dose 2) 8 months (dose 3) 18 months (dose 4) Haemophilus influenza b (Hib) 6 months (dose 1) 1 month 4 7 months (dose 2) 8 months (dose 3) 18 months (dose 4) Hepatitis B (HB) 6 months (dose 1) 1–2 months 4 7 months (dose 2) 8 months (dose 3) 18 months (dose 4) Meningococcus (MACWY) (MB) 12 months (dose 1) 12 months (12 and 18 months) 2 18 months (dose 2) Pneumococcus (PN13) Sequential schedule: PN13: 1–2 months 3 3 months (dose 1) 1 4 months (dose 2) 5 months (dose 3) (PN23) PN23: 2 months after PN13 2 12–24 months (dose 1) 5 years after first dose of PN23 (dose 2) Hepatitis A (HA) 6 months (dose 1) 6 months 2 12 months (dose 2) Influenza 4–6 months (influenza season) 1 month in first time vaccination of 1 (2 in first-time vaccination patients younger than 9 years of patients younger than 9 years) Papilloma virus (HPV) 12 months (dose 1) 1–2 months (between dose 1 and 2) 3 13–14 months (dose 2) 4 months (between dose 2 and 3) 18 months (dose 3) Measles, mumps and rubella 24 months (only if no immunosu- 1 month 2 (MMR) pression or graft versus host dis- ease are present and cell immunity is reconstituted) 24 months (dose 1) 25 months (dose 2) Varicella (VZ) 24 months (only if no immunosu- 1 month 2 pression or graft versus host dis- ease are present and cell immunity is reconstituted) 24 months (dose 1) 25 months (dose 2) HA hepatitis A vaccine, HSCT hematopoietic stem cell transplantation, MACWY​ meningococcal A, C, W and Y vaccine, MB meningococcal B vaccine, MMR measles, mumps and rubella vaccine, HPV human papillomavirus vaccine, PN13 pneumococcal conjugated vaccine, PN23 pneu- mococcal polysaccharide vaccine, VZ varicella vaccine • Immunoglobulin replacement therapy may reduce the Once B-cell aplasia is resolved, the vaccination program immunogenicity of vaccines. Therefore, in case of vacci- should be started [97]. The immune response in this scenario nation, it should be done between 1 week and 24 h before is unknown. As in post-HSCT patients, combined vaccines the next immunoglobulin infusion. could be used to improve immunological response [99–101]. 13 I. Los‑Arcos et al. Table 4  Proposed calendar for Visit Vaccines Observations post-CAR T patients who have undergone HSCT Visit 1 a Hexavalent (1) 6 months after HSCT PN13 (1) Influenzab (1) Visit 2 Hexavalent (2) 1 month after visit 1 PN13 (2) Visit 3 Hexavalent (3) 1 month after visit 2 PN13 (3) HA (1) Visit 4 MB (1) 2 months after visit 3 and also 12 months after MACWY (1) HPV (1) Visit 5 PN23 (1) 1 month after visit 4 HPV (2) Visit 6 MB (2) 6 months after visit 4 and 4 months after visit 5 MACWY (2) HA (2) HPV (3) Hexavalent (4) Visit 7 MMR (1) 24 months after BMT, with no immunosuppressant therapy or VZ (1) graft versus host disease present, and cell immunity reconsti- tuted Visit 8 MMR (2) 2 months after visit 7 VZ (2) All visits programmed assuming HSCT performed more than 6 months before, B-cell depletion resolved and immunoglobulin production confirmed a HA: hepatitis A vaccine; HSCT: hematopoietic stem cell transplantation; HEXAVALENT: vaccine against diphtheria, tetanus, pertussis, Haemophilus influenza b, poliovirus and hepatitis B; MACWY: meningococ- cal A, C, W and Y vaccine; MB; meningococcal B vaccine; MMR: measles, mumps and rubella vaccine; HPV: human papillomavirus vaccine; PN13: pneumococcal conjugated vaccine; PN23: pneumococcal pol- ysaccharide vaccine; VZ; varicella vaccine b Influenza vaccination (one dose) can be scheduled as soon as possible. In patients younger than 9 years old who are receiving it for the first time, two doses should be administered separated by one month In those who have not undergone HSCT, the vaccine Acknowledgements Collaborators (Infection Prevention in CAR program should include (if not administered before the cell T-cells Study Group): Javier Briones Meijide (Hospital de la Santa Creu i Sant Pau, Barcelona, Spain), Julio Delgado (Hospital Clínic, infusion): Barcelona, Spain), Natalia Mendoza-Palomar (Hospital Universitari Vall d’Hebron, Barcelona, Spain), Marta Moreno Alonso (Hospital La • Influenza in epidemic season. Fé, Valencia, Spain), Susana Rives (Hospital Sant Joan de Déu, Barce- • Anti-pneumococcal sequential vaccination: one dose of lona, Spain), Patricia Muñoz (Hospital General Universitario Gregorio Marañón, Madrid, Spain). conjugated vaccine, followed by one dose of polysac- charide vaccine a minimum of 8 weeks after. A second Funding This research received no specific grant from any funding dose of polysaccharide vaccine should be administered agency in the public, commercial, or not-for-profit sectors. a minimum of 5 years after the first dose. • HBV, especially in susceptible patients with high risk of Compliance with ethical standards infection or reactivation, and in areas of high prevalence of this infection. Conflict of interest ILA declares having received travel support from • Other inactivated vaccines may be indicated if other risk Gilead, MSD and Novartis, and speaker honoraria from Pfizer, out- side the submitted work. GI declares honoraria from Gilead, Novartis, factors are present (i.e., hepatitis A vaccine in patients Roche and Celgene. CDH declares having received travel grants with chronic liver disease, Haemophilus influenzae b and from MSD, Gilead, Novartis Jazz Pharmaceuticals, Consultancy de meningococcal vaccines in asplenic patients, etc.) Novartis and Amgen, and speaker fees from Novartis, Jazz Pharma- ceuticals and Sobi. JLRO received travel grants from Novartis, Gilead and Celgene. VOM is a recipient of a research grant (FEHH), travel In those who have undergone HSCT, the proposed vacci- grants (Kite, Celgene, Novartis, Roche, Takeda & Janssen), consultant nation schedule is prepared according to the model of HSCT or advisory fees (Kite, Celgene, Novartis) and honoraria (Kite). PSP patients (Tables 3, 4). reports grants, personal fees and non-financial support from Gilead, 13 Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… Pfizer, MSD and Astellas Pharma, outside the submitted work. PB 14. Nastoupil LJ, Jain MD, Feng L, Spiegel JY, Ghobadi A, Lin Y, declares having received honoraria from Amgen, Celgene, Gilead, et al. Standard-of-care axicabtagene ciloleucel for relapsed or Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, not refractory large B-cell lymphoma: results from the US lymphoma related with the present article. IRC declares having received honoraria CAR T consortium. J Clin Oncol. 2020; JCO1902104. from, Celgene, Gilead, MSD, Astellas, Novartis, and Pfizer outside 15. Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, the submitted work. The rest of the authors declare that they have no et al. Infectious complications of CD19-targeted chimeric conflict of interest. antigen receptor-modified T-cell immunotherapy. Blood. 2018;131:121–30. 16. Pasquini MC, Locke FL, Herrera AF, Siddiqi T, Ghobadi A, Komanduri KV, et al. Post-marketing use outcomes of an anti- CD19 chimeric antigen receptor (CAR) T cell therapy, axicabta- References gene ciloleucel (Axi-Cel), for the treatment of large B cell lym- phoma (LBCL) in the United States (US). Blood. 2019;134:764. 1. Bondanza A, Bonini C, Fehse B, Hudecek M. Cellular therapy 17. Yescarta EMA product information [Internet]. [cited 2020 Feb with engineered T cells, efficacy and side effects. In: Carreras E, 12]. https​://www.ema.europ​a.eu/en/docum​ents/produ​ct-infor​ Dufour C, Mohty M, Kröger N, editors. The EBMT handbook. mation​ /yescar​ ta-epar-produc​ t-inform ​ ation​ _en.pdf. Accessed Feb 7th ed. Berlin: Springer; 2019. p. 449–455. 2020. 2. Forman SJ, Kalos M, June CH. Adoptive T‐cell therapy for 18. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bitten- malignancy in the setting of hematopoietic cell transplantation. court H, et al. Tisagenlecleucel in children and young adults with In: Antin JH, Appelbaum FR, Forman SJ, Negrin RS, editors. B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48. Thomas’ hematopoietic cell transplantion. 5th ed. Wiley-Black- 19. Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van well; 2016. p. 826–35. Vollenhoven RF. Integrated safety in tocilizumab clinical trials. 3. Mahadeo KM, Khazal SJ, Abdel-Azim H, Fitzgerald JC, Tarase- Arthritis Res Ther. 2011;13:R141. viciute A, Bollard CM, et al. Management guidelines for paedi- 20. Frigault MJ, Nikiforow S, Mansour MK, Hu ZH, Horowitz MM, atric patients receiving chimeric antigen receptor T cell therapy. Riches ML, et al. Tocilizumab not associated with increased Nat Rev Clin Oncol. 2019;16:45–63. infection risk after CAR T-cell therapy: implications for COVID- 4. Budde LE, Zaia JA. CD19 CAR-T therapy and sepsis: dancing 19? Blood. 2020;136:137–9. with the devil. Blood. 2018;131:7–8. 21. Strati P, Ahmed S, Kebriaei P, Nastoupil LJ, Claussen CM, Wat- 5. Wang Z, Han W. Biomarkers of cytokine release syndrome son G, et al. Clinical efficacy of anakinra to mitigate CAR T-cell and neurotoxicity related to CAR-T cell therapy. Biomark Res. therapy–associated toxicity in large B-cell lymphoma. Blood 2018;6:4. Adv. 2020;4:3123–7. 6. Trzeciak A, Pietropaoli AP, Kim M. Biomarkers and associ- 22. Salliot C, Dougados M, Gossec L. Risk of serious infections dur- ated immune mechanisms for early detection and therapeutic ing rituximab, abatacept and anakinra treatments for rheumatoid management of sepsis. Immune Netw Korean Assoc Immunol. arthritis: meta-analyses of randomised placebo-controlled trials. 2020;20:e23. Ann Rheum Dis. 2009;68:25–322. 7. Park JH, Romero FA, Taur Y, Sadelain M, Brentjens RJ, Hohl 23. Winthrop KL, Mariette X, Silva JT, Benamu E, Calabrese LH, TM, et al. Cytokine release syndrome grade as a predictive Dumusc A, et al. ESCMID Study Group for Infections in Com- marker for infections in patients with relapsed or refractory promised Hosts (ESGICH) Consensus Document on the safety B-cell acute lymphoblastic leukemia treated with chimeric anti- of targeted and biological therapies: an infectious diseases gen receptor T cells. Clin Infect Dis. 2018;67:533–40. perspective (soluble immune effector molecules [II]: agents 8. Luo H, Wang N, Huang L, Zhou X, Jin J, Li C, et al. Inflam- targeting interleukins. Immunoglobuli Clin Microbiol Infect. matory signatures for quick diagnosis of life-threatening infec- 2018;21:S21–40. tion during the CAR T-cell therapy. J Immunother Cancer. 24. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, 2019;7:271. et al. Chimeric antigen receptor T cells for sustained remissions 9. Kymriah EMA product information [Internet] [cited 2020 Feb in leukemia. N Engl J Med. 2014;371:1507–17. 12]. https​://www.ema.europ​a.eu/en/docum​ents/produ​ct-infor​ 25. Doan A, Pulsipher MA. Hypogammaglobulinemia due to CAR matio​n/kymri​ah-epar-produ​ct-infor ​matio​n_en.pdf. Accessed T-cell therapy. Pediatr Blood Cancer. 2018;65:e26914. Feb 2020. 26. Vora SB, Waghmare A, Englund JA, Qu P, Gardner RA, Hill 10. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, JA. Infectious complications following CD19 chimeric antigen Oluwole OO, et al. Long-term safety and activity of axicabta- receptor T-cell therapy for children, adolescents, and young gene ciloleucel in refractory large B-cell lymphoma (ZUMA- adults. Open Forum Infect Dis. 2020;7:ofaa121. 1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 27. Gardner RA, Finney O, Annesley C, Brakke H, Summers C, 2019;20:31–42. Leger K, et al. Intent-to-treat leukemia remission by CD19 CAR 11. Logue JM, Zucchetti E, Bachmeier CA, Krivenko GS, Larson V, T cells of defined formulation and dose in children and young Ninh D, et al. Immune reconstitution and associated infections adults. Blood. 2017;129:3322–31. following axicabtagene ciloleucel in relapsed or refractory large 28. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak B-cell lymphoma. Haematologica. 2020 (Online ahead of print). Ö, et al. Chimeric antigen receptor T cells in refractory B-cell 12. Wudhikarn K, Palomba ML, Pennisi M, Garcia-Recio M, Flynn lymphomas. N Engl J Med. 2017;377:2545–54. JR, Devlin SM, et al. Infection during the first year in patients 29. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, treated with CD19 CAR T cells for diffuse large B cell lym- Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell phoma. Blood Cancer J. 2020;10:79. therapy in refractory large B-cell lymphoma. N Engl J Med. 13. Cordeiro A, Bezerra ED, Hirayama AV, Hill JA, Wu QV, Vout- 2017;377:2531–44. sinas J, et al. Late events after treatment with CD19-targeted 30. Bhoj VG, Arhontoulis D, Wertheim G, Capobianchi J, Calla- chimeric antigen receptor modified T cells. Biol Blood Marrow han CA, Ellebrecht CT, et al. Persistence of long-lived plasma Transplant. 2020;26:26–33. cells and humoral immunity in individuals responding to CD19- directed CAR T-cell therapy. Blood. 2016;128:360–70. 13 I. Los‑Arcos et al. 31. Hill JA, Giralt S, Torgerson TR, Lazarus HM. CAR-T—and a side 46. Gentile G, Andreoni M, Antonelli G, Sarmati L. Screening, order of IgG, to go?—Immunoglobulin replacement in patients monitoring, prevention, prophylaxis and therapy for hepati- receiving CAR-T cell therapy. Blood Rev. 2019;38:100596. tis B virus reactivation in patients with haematologic malig- 32. Kansagra AJ, Frey NV, Bar M, Laetsch TW, Carpenter PA, nancies and patients who underwent haematologic stem cell Savani BN, et al. Clinical utilization of chimeric antigen recep- transplantation: a systematic review. Clin Microbiol Infect. tor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia 2017;23:916–23. (ALL)—an expert opinion from the European Society for Blood 47. Totani H, Kusumoto S, Ishida T, Masuda A, Yoshida T, Ito and Marrow Transplantation (EBMT) and the American Soci- A, et al. Reactivation of hepatitis B virus (HBV) infection in ety for Blood and Marrow Transplant. Bone Marrow Transplant. adult T-cell leukemia-lymphoma patients with resolved HBV 2019;54:1868–80. infection following systemic chemotherapy. Int J Hematol. 33. Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic 2015;101:398–404. IgG level in primary immunodeficiency disease: the IgG level 48. Seto W-K, Chan TS-Y, Hwang Y-Y, Wong DK-H, Fung J, Liu that protects against recurrent infection. J Allergy Clin Immunol. KS-H, et al. Hepatitis B reactivation in occult viral carriers 2008;122:210–2. undergoing hematopoietic stem cell transplantation: a prospec- 34. Björkander J, Hammarström L, Smith CI, Buckley RH, Cun- tive study. Hepatology. 2017;65:1451–61. ningham-Rundles C, Hanson LA. Immunoglobulin prophylaxis 49. Mallet V, van Bömmel F, Doerig C, Pischke S, Hermine O, in patients with antibody deficiency syndromes and anti-IgA Locasciulli A, et al. Management of viral hepatitis in patients antibodies. J Clin Immunol. 1987;7:8–15. with haematological malignancy and in patients undergoing 35. Sundin U, Nava S, Hammarström L. Induction of unrespon- haemopoietic stem cell transplantation: recommendations of the siveness against IgA in IgA-deficient patients on subcutane- 5th European Conference on Infections in Leukaemia (ECIL-5). ous immunoglobulin infusion therapy. Clin Exp Immunol. Lancet Infect Dis Lancet Publish Group. 2016;16:606–17. 1998;112:341–6. 50. Hill JA, Seo SK. How I prevent infections in patients receiv- 36. Hernandez-Trujillo HS, Chapel H, Lo Re V, Notarangelo LD, ing CD19-targeted chimeric antigen receptor T cells for B-cell Gathmann B, Grimbacher B, et al. Comparison of American and malignancies. Blood. 2020;136:925–35. European practices in the management of patients with primary 51. Hwang JP, Torres HA. Hepatitis B virus and hepatitis C virus immunodeficiencies. Clin Exp Immunol. 2012;169:57–69. infection in immunocompromised patients. Curr Opin Infect Dis 37. Gutiérrez-Gutiérrez B, Salamanca E, de Cueto M, Hsueh P-R, NLM (Medline). 2018;31:535–41. Viale P, Paño-Pardo JR, et al. Effect of appropriate combina- 52. Pawlotsky J-M, Negro F, Aghemo A, Berenguer M, Dalgard O, tion therapy on mortality of patients with bloodstream infec- Dusheiko G, et al. EASL recommendations on treatment of hepa- tions due to carbapenemase-producing Enterobacteriaceae titis C 2018. J Hepatol. 2018;69:461–511. (INCREMENT): a retrospective cohort study. Lancet Infect Dis. 53. Hayden PJ, Sirait T, Koster L, Snowden JA, Yakoub-Agha I. An 2017;17:726–34. international survey on the management of patients receiving 38. Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, CAR T-cell therapy for haematological malignancies on behalf et al. Update on the use of immunoglobulin in human disease: a of the chronic malignancies working party of EBMT. Curr Res review of evidence. J Allergy Clin Immunol. 2017;139:S1–46. Transl Med. 2019;67:79–88. 39. Cardozo C, Delgado J, Ortiz-Maldonado V, Puerta-Alcalde P, 54. Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig Urbano-Ispizua A, Juan M, Esteve J, Soriano A, Garcia-Vidal C. H, Ciceri F, et al. Management of adults and children under- Infections in haematological patients receiving chimeric antigen going chimeric antigen receptor T-cell therapy: best prac- receptor T cell immunotherapy. Oral Session 00802:90 (Final tice recommendations of the European Society for Blood and progr) Marrow Transplantation (EBMT) and the Joint Accreditation 40. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, Committee of ISCT and EBMT (JACIE). Haematologica. McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory 2020;105:297–316. diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45–56. 55. Abramson JS, Irwin KE, Frigault MJ, Dietrich J, McGree B, Jor- 41. Korr G, Thamm M, Czogiel I, Poethko-Mueller C, Bremer V, dan JT, et al. Successful anti-CD19 CAR T-cell therapy in HIV- Jansen K. Decreasing seroprevalence of herpes simplex virus infected patients with refractory high-grade B-cell lymphoma. type 1 and type 2 in Germany leaves many people susceptible to Cancer. 2019;125:3692–8. genital infection: time to raise awareness and enhance control. 56. Abbasi A, Peeke S, Shah N, Mustafa J, Khatun F, Lombardo BMC Infect Dis. 2017;17:471. A, et al. Axicabtagene ciloleucel CD19 CAR-T cell therapy 42. Shih CA, Chen WC, Yu HC, Cheng JS, Lai KH, Hsu JT, et al. results in high rates of systemic and neurologic remissions in Risk of severe acute exacerbation of chronic HBV infection can- ten patients with refractory large B cell lymphoma including two cer patients who underwent chemotherapy and did not receive with HIV and viral hepatitis. J Hematol Oncol. 2020;13:1. anti-viral prophylaxis. PLoS ONE. 2015;10:e0132426. 57. WHO [Internet]. 2017 [cited 2017 Aug 28]. https​://www.who. 43. Strati P, Nastoupil LJ, Fayad LE, Samaniego F, Adkins S, Nee- int/en. Accessed Feb 2020. lapu SS. Safety of CAR T-cell therapy in patients with B-cell 58. Williams JV, Martino R, Rabella N, Otegui M, Parody R, Heck lymphoma and chronic hepatitis B or C virus infection. Blood. JM, et al. A prospective study comparing human metapneu- 2019;133:2800–2. movirus with other respiratory viruses in adults with hemato- 44. Wei J, Zhu X, Mao X, Huang L, Meng F, Zhou J. Severe early logic malignancies and respiratory tract infections. J Infect Dis. hepatitis B reactivation in a patient receiving anti-CD19 and 2005;192:1061–5. anti-CD22 CAR T cells for the treatment of diffuse large B-cell 59. Debur MC, Vidal LR, Stroparo E, Nogueira MB, Almeida SM, lymphoma. J Immunother cancer. 2019;7:315. Takahashi GA, et al. Human metapneumovirus infection in 45. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter hematopoietic stem cell transplant recipients. Transpl Infect Dis. YT, American Gastroenterological Association Institute. 2010;12:173–9. American Gastroenterological Association Institute guideline 60. Shah DP, Ghantoji SS, Ariza-Heredia EJ, Shah JN, El Taoum on the prevention and treatment of hepatitis B virus reactiva- KK, Shah PK, et al. Immunodeficiency scoring index to predict tion during immunosuppressive drug therapy. Gastroenterol- poor outcomes in hematopoietic cell transplant recipients with ogy. 2015;148:215–9 (quiz e16–7). RSV infections. Blood. 2014;123:3263–8. 13 Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… 61. Pinaña JL, Perez A, Montoro J, Gimenez E, Gómez MD, Lorenzo 77. Ljungman P, Mikulska M, de la Camara R, Basak GW, Cha- I, et al. Clinical effectiveness of influenza vaccination after allo- bannon C, Corbacioglu S, et al. The challenge of COVID-19 geneic hematopoietic stem cell transplantation: a cross-sectional, and hematopoietic cell transplantation; EBMT recommenda- prospective. Obser Study Clin Infect Dis. 2019;68:1894–903. tions for management of hematopoietic cell transplant recipi- 62. Kmeid J, Vanichanan J, Shah DP, El Chaer F, Azzi J, Ariza-Here- ents, their donors, and patients undergoing CAR T-cell therapy. dia EJ, et al. Outcomes of influenza infections in hematopoietic Bone Marrow Transplant. 2020. https​://doi.org/10.1038/s4140​ cell transplant recipients: application of an immunodeficiency 9-020-0919-0. scoring index. Biol Blood Marrow Transplant. 2016;22:542–8. 78. Infectious Diseases Society of America Guidelines on the Treat- 63. Wang L, Allen J, Diong C, Goh YT, Gopalakrishnan S, Ho A, ment and Management of Patients with COVID-19 [Internet]. et al. Respiratory virus infection after allogeneic hematopoi- [cited 2020 Aug 12]. Available from: https​://www.idsoc​iety. etic stem cell transplant in a tropical center: predictive value org/pract​ice-guide​line/covid​-19-guide​line-treat​ment-and-manag​ of the immunodeficiency scoring index. Transpl Infect Dis. ement​/. Accessed Aug 2020. 2017;19:e12693. 79. Bachanova V, Bishop MR, Dahi P, Dholaria B, Grupp SA, Hayes- 64. Spahr Y, Tschudin-Sutter S, Baettig V, Compagno F, Tamm M, Lattin B, et al. Chimeric antigen receptor T cell therapy dur- Halter J, et al. Community-acquired respiratory paramyxovirus ing the COVID-19 pandemic. Biol Blood Marrow Transplant. infection after allogeneic hematopoietic cell transplantation: a 2020;26:1239–46. single-center experience. Open Forum Infect Dis. 2018;5:ofy077. 80. Walls T, Hawrami K, Ushiro-Lumb I, Shingadia D, Saha V, 65. Khanna N, Steffen I, Studt JD, Schreiber A, Lehmann T, Weis- Shankar AG. Adenovirus infection after pediatric bone marrow ser M, et al. Outcome of influenza infections in outpatients after transplantation: is treatment always necessary? Clin Infect Dis. allogeneic hematopoietic stem cell transplantation. Transpl Infect 2005;40:1244–9. Dis. 2009;11:100–5. 81. Runde V, Ross S, Trenschel R, Lagemann E, Basu O, Renzing- 66. Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch Köhler K, et al. Adenoviral infection after allogeneic stem cell HH, Cordonnier C, et al. European guidelines for diagnosis transplantation (SCT): report on 130 patients from a single SCT and treatment of adenovirus infection in leukemia and stem unit involved in a prospective multi center surveillance study. cell transplantation: summary of ECIL-4. Transpl Infect Dis. Bone Marrow Transplant. 2001;28:51–7. 2011;2012:555–63. 82. Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, 67. Chakrabarti S, Collingham KE, Holder K, Oyaide S, Pillay D, Hill JA, et al. Guidelines for the management of cytomegalovi- Milligan DW. Parainfluenza virus type 3 infections in hematopo- rus infection in patients with haematological malignancies and etic stem cell transplant recipients: response to ribavirin therapy. after stem cell transplantation from the 2017 European Confer- Clin Infect Dis. 2000;31:1516–8. ence on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 68. Stankova J, Carret AS, Moore D, McCusker C, Mitchell D, 2019;19:e260–e272272. Davis M, et al. Long-term therapy with aerosolized ribavirin 83. Hiwarkar P, Kosulin K, Cesaro S, Mikulska M, Styczynski J, for parainfluenza 3 virus respiratory tract infection in an infant Wynn R, et al. Management of adenovirus infection in patients with severe combined immunodeficiency. Pediatr Transplant. after haematopoietic stem cell transplantation: State-of-the-art 2007;11:209–13. and real-life current approach: a position statement on behalf 69. Sparrelid E, Ljungman P, Ekelöf-Andström E, Aschan J, Ringdén of the infectious diseases working party of the European soci- O, Winiarski J, et al. Ribavirin therapy in bone marrow transplant ety of blood and marrow transplantation. Rev Med Virol. recipients with viral respiratory tract infections. Bone Marrow 2018;28:e1980. Transplant. 1997;19:905–8. 84. Marty FM, Winston DJ, Chemaly RF, Mullane KM, Shore TB, 70. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical fea- Papanicolaou GA, et al. A randomized, double-blind, placebo- tures of patients infected with 2019 novel coronavirus in Wuhan, controlled phase 3 trial of oral brincidofovir for cytomegalovirus China. Lancet. 2020;395:497–506. prophylaxis in allogeneic hematopoietic cell transplantation. Biol 71. Coronavirus disease 2019 (COVID-19) Situation report-133. Blood Marrow Transplant. 2019;25:369–81. World Health Organization [Internet]. [cited 2020 Jun 2]. https​ 85. Hill JB, Sheffield JS, McIntire DD, Wendel GD. Acute pyelone- ://www.who.int/docs/defau​lt-sourc​e/coron​aviru​se/situa​tion- phritis in pregnancy. Obstet Gynecol. 2005;105:18–23. repor​ts/20200​601-covid​-19-sitre​p-133.pdf?sfvrs​n=9a56f​2ac_4. 86. Haidar G, Dorritie K, Farah R, Bogdanovich T, Nguyen MH, Accessed June 2020. Samanta P. Invasive mold infections after chimeric antigen recep- 72. Siddiqi HK, Mehra MR. COVID-19 illness in native and immu- tor-modified T-cell therapy: a case series, review of the literature, nosuppressed states: a clinical—therapeutic staging proposal. J and implications for prophylaxis. Clin Infect Dis. 2019;71:672–6. Hear Lung Transplant. 2020;39:405–7. 87. Donnelly JP, Leeflang MM. Galactomannan detection and diag- 73. Malard F, Genthon A, Brissot E, van de Wyngaert Z, Marjanovic nosis of invasive Aspergillosis. Clin Infect Dis. 2010;50:1070–1. Z, Ikhlef S, et al. COVID-19 outcomes in patients with hemato- 88. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, logic disease. Bone Marrow Transplant. 2020 (online ahead of Walsh TJ, et al. Posaconazole vs. fluconazole or itracona- print). zole prophylaxis in patients with neutropenia. N Engl J Med. 74. Martín-Moro F, Marquet J, Piris M, Michael BM, Sáez AJ, 2007;356:348–59. Corona M, et al. Survival study of hospitalized patients with 89. Duarte RF, Sánchez-Ortega I, Cuesta I, Arnan M, Patiño B, concurrent Covid-19 and haematological malignancies. Br J Hae- Fernández de Sevilla A, et al. Serum galactomannan-based matol. 2020;190:bjh16801. early detection of invasive aspergillosis in hematology patients 75. He W, Chen L, Chen L, Yuan G, Fang Y, Chen W, et al. receiving effective antimold prophylaxis. Clin Infect Dis. COVID-19 in persons with haematological cancers. Leukemia. 2014;59:1696–702. 2020;34:1637–45. 90. Vena A, Bouza E, Álvarez-Uría A, Gayoso J, Martín-Rabadán P, 76. Ardura M, Hartley D, Dandoy C, Lehmann L, Jaglowski S, Cajuste F, et al. The misleading effect of serum galactomannan Auletta JJ. Addressing the impact of the coronavirus disease testing in high-risk haematology patients receiving prophylaxis 2019 (COVID-19) pandemic on hematopoietic cell transplanta- with micafungin. Clin Microbiol Infect. 2017;23:1000.e1–.e4. tion: learning networks as a means for sharing best practices. 91. Mahmoudjafari Z, Hawks KG, Hsieh AA, Plesca D, Gat- Biol Blood Marrow Transplant. 2020;26:e147–e160160. wood KS, Culos KA. American society for blood and marrow 13 I. Los‑Arcos et al. transplantation pharmacy special interest group survey on chi- warning signs, diagnosis, and management. Front Immunol. meric antigen receptor T cell therapy administrative, logistic, and 2019;10:586. toxicity management practices in the United States. Biol Blood 97. Documento de consenso internacional, Comité Asesor de Vacu- Marrow Transplant. 2019;25:26–33. nas de la AEP. Año 2016 [Internet]. 2016. Available from: https​ 92. Sánchez-Montalvá A, Salvador F, Ruiz-Camps I, Barba P, Val- ://vacun​asaep​.org/profe​siona​les/notic​ias/conse​nso-vacun​acion​ cárcel D, Sulleiro E, et al. Imported disease screening prior to -situa​cione​s-espec​iales​. Accessed Aug 2020. chemotherapy and bone marrow transplantation for oncohema- 98. Chong CR, Park V, Harding JJ, Brite J, Wolchok JD, Kam- tological malignancies. Am J Trop Med Hyg. 2016;95:1463–8. boj M. Safety of influenza vaccination in patients undergoing 93. Buitrago J, Adkins S, Hawkins M, Iyamu K, Oort T. Adult sur- immunotherapy treatment for advanced cancer. J Clin Oncol. vivorship: considerations following CAR T-cell therapy. Clin J 2018;36:e15073. Oncol Nurs. 2019;23:42–8. 99. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tom- 94. Peremiquel-Trillas P, Leguízamo LM, Asensio Ostos C, Mar- blyn M, et al. Executive summary: 2013 IDSA clinical practice tínez-Gómez X. Vacunas para pacientes en tratamiento con guideline for vaccination of the immunocompromised host. Clin fármacos inmunodepresores, inmunomoduladores o biológicos. Infect Dis. 2014;58:309–18. Med Clin (Barc). 2018;151:498–502. 100. Carpenter PA, Englund JA. How I vaccinate blood and marrow 95. National Comprehensive Cancer Network. NCCN Clinical Prac- transplant recipients. Blood. 2016;127:2824–32. tice Guidelines in Oncology (NCCN Guidelines): Prevention and 101. Guidelines for vaccination of patients with hematological malig- treatment of cancer-related infections [v.2.2016] 2016. nances and HSTC recipients. 7 European Conference on Infec- 96. Sánchez-Ramón S, Bermúdez A, González-Granado LI, Rod- tions in Leukaemia (ECIL), 22–23 Sep 2017, Juan-Les-Pins ríguez-Gallego C, Sastre A, Soler-Palacín P, et al. Primary and France. secondary immunodeficiency diseases in oncohaematology: Affiliations Ibai Los‑Arcos1,2 · Gloria Iacoboni3 · Manuela Aguilar‑Guisado5 · Laia Alsina‑Manrique6 · Cristina Díaz de Heredia7 · Claudia Fortuny‑Guasch8 · Irene García‑Cadenas9 · Carolina García‑Vidal10 · Marta González‑Vicent11 · Rafael Hernani12 · Mi Kwon13 · Marina Machado14 · Xavier Martínez‑Gómez15 · Valentín Ortiz Maldonado16,17 · Carolina Pinto Pla18 · José Luis Piñana19 · Virginia Pomar20 · Juan Luis Reguera‑Ortega21 · Miguel Salavert22 · Pere Soler‑Palacín23 · Lourdes Vázquez‑López24 · Pere Barba3,4 · Isabel Ruiz‑Camps1,2 1 11 Infectious Diseases Department, Hospital Universitari Vall Hematopoietic Stem Cell Transplantation and Cellular D’Hebron, Barcelona, Spain Therapy Unit, Hospital Infantil Universitario “Niño Jesus”, 2 Madrid, Spain Department of Medicine, Universitat Autònoma de 12 Barcelona, Barcelona, Spain Department of Hematology, Hospital Clínico Universitario, 3 Institute for Research INCLIVA, Valencia, Spain Deparment of Hematology, Vall D’Hebron Institute 13 of Oncology (VHIO), Hospital Universitari Vall D’Hebron, Haematology and Haemotherapy Department, Hospital Barcelona, Spain General Universitario Gregorio Marañón, Gregorio Marañón 4 Health Research Institute, Madrid, Spain Department of Medicine, Universitat Autònoma de 14 Barcelona, Passeig Vall d’Hebron 119‑129, 08035 Barcelona, Clinical Microbiology and Infectious Diseases, Hospital Spain General Universitario Gregorio Marañón, Gregorio Marañón 5 Health Research Institute, Madrid, Spain Department of Infectious Diseases, Microbiology 15 and Preventive Medicine, University Hospital Virgen del Epidemiology Department, Vall D’Hebron University Rocío/CSIC/Institute of Biomedicine of Seville (IBIS), Hospital, Universitat Autònoma de Barcelona, Barcelona, Seville, Spain Spain 6 16 Clinical Immunology and Primary Immunodeficiencies Unit, Department of Hematology, Hospital Clínic de Barcelona, Hospital Sant Joan de Deu, Barcelona, Spain Institut D’Investigacions Biomèdiques August Pi I Sunyer 7 (IDIBAPS), University of Barcelona, Barcelona, Spain Paediatric Oncology and Hematology Department, 17 Hematopoietic Stem Cell Transplantation, Hospital Centro de Investigación Biomédica en Red de Cáncer Universitari Vall D’Hebron, Barcelona, Spain (CIBERONC), University of Barcelona, Barcelona, Spain 8 18 Infectious Diseases Unit, Hospital Sant Joan de Deu, Infectious Diseases Unit, Hospital Clínico Universitario, Barcelona, Spain Instituto de Investigación INCLIVA, Valencia, Spain 9 19 Hematology Department, Hospital de La Santa Creu I Hematology Division, Hospital Universitario Y politécnico Sant Pau, Sant Pau and Jose Carreras Leukemia Research La Fe, Instituto de investigación sanitaria La Fe, Valencia, Institutes, Autonomous University of Barcelona, Barcelona, CIBERONC, Instituto Carlos III, Madrid, Spain Spain 20 Infectious Disease Unit, Internal Medicine Department, 10 Department of Infectious Diseases, Hospital Clínic, Hospital de La Santa Creu I Sant Pau, Barcelona, Spain IDIBAPS (Institut D’Investigacions biomèdiques Agust Pi I Sunyer), Universitat de Barcelona, Barcelona, Spain 13 Recommendations for screening, monitoring, prevention, and prophylaxis of infections in… 21 23 Department of Haematology, University Hospital Virgen Pediatric Infectious Diseases and Immunodeficiencies Unit, del Rocío/CSIC/Institute of Biomedicine of Seville (IBIS), Hospital, Universitari Vall D’Hebron, Barcelona, Spain Seville, Spain 24 Department of Haematology, University Hospital 22 Infectious Diseases Unit, Área Clínica Médica, Hospital of Salamanca, Salamanca, Spain Universitario Y Politécnico La Fe, Valencia, Spain 13